Regulation of the RNAPII Pool Is Integral to the DNA Damage Response.

In response to transcription-blocking DNA damage, cells orchestrate a multi-pronged reaction, involving transcription-coupled DNA repair, degradation of RNA polymerase II (RNAPII), and genome-wide transcription shutdown. Here, we provide insight into how these responses are connected by the finding that ubiquitylation of RNAPII itself, at a single lysine (RPB1 K1268), is the focal point for DNA-damage-response coordination. K1268 ubiquitylation affects DNA repair and signals RNAPII degradation, essential for surviving genotoxic insult. RNAPII degradation results in a shutdown of transcriptional initiation, in the absence of which cells display dramatic transcriptome alterations. Additionally, regulation of RNAPII stability is central to transcription recovery-persistent RNAPII depletion underlies the failure of this process in Cockayne syndrome B cells. These data expose regulation of global RNAPII levels as integral to the cellular DNA-damage response and open the intriguing possibility that RNAPII pool size generally affects cell-specific transcription programs in genome instability disorders and even normal cells. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Ana Tufegdžić Vidaković, Richard Mitter, Gavin P Kelly, Michelle Neumann, Michelle Harreman, Marta Rodríguez-Martínez, Anna Herlihy, Juston C Weems, Stefan Boeing, Vesela Encheva, Liam Gaul, Laura Milligan, David Tollervey, Ronald C Conaway, Joan W Conaway, Ambrosius P Snijders, Aengus Stewart, Jesper Q Svejstrup. Regulation of the RNAPII Pool Is Integral to the DNA Damage Response. Cell. 2020 Mar 19;180(6):1245-1261.e21

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PMID: 32142654

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